Is MTHFD1 p.Val214Phe (c.640G>T) pathogenic?

MTHFD1 p.Val214Phe (c.640G>T) is classified Uncertain significance in MTHFD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-06-19). AlphaMissense: likely pathogenic (0.7635); Absent from gnomAD v4.1; Associated with Inborn genetic diseases.

What condition is associated with MTHFD1 p.Val214Phe (c.640G>T)?

MTHFD1 p.Val214Phe (c.640G>T) is associated with Inborn genetic diseases (ClinVar).

How common is MTHFD1 p.Val214Phe (c.640G>T) in the general population?

MTHFD1 p.Val214Phe (c.640G>T) is absent from gnomAD v4.1 (gnomAD).

What do computational predictors say about MTHFD1 p.Val214Phe (c.640G>T)?

AlphaMissense predicts likely pathogenic (score 0.7635) — an in-silico prediction, not a clinical call.

MTHFD1 p.Val214Phe

c.640G>T · VCV4111766

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely pathogenic

0.7635 · ACMG-weighted

gnomAD v4.1

Absent

absent from gnomAD v4.1

Missense predictors

2/2 damaging

AlphaMissense, SaProt · REVEL no call

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.7635	likely pathogenic
REVEL	0.562	indeterminate
SaProt	LLR -13.25	damaging
⇒ AlphaMissense and SaProt both call this damaging; REVEL makes no call.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 12	GERP 2.1, phastCons 1
Regional constraint	o/e 0.83	unconstrained · MANE · 39 kb · p 0.00013 · regional, not allelic
Overall
CADD	28.3	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean damaging — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Absent from gnomAD v4.1. Not observed in any sequenced alleles — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

Variant & gene context

Gene: MTHFD1
Protein: p.Val214Phe
Coding: c.640G>T
MANE Select: NM_005956
Type: single nucleotide variant
Location: chr14:64419838 (GRCh38)
Gene constraint: LOEUF 0.51 · pLI 0.83 (gnomAD)
Structure: AlphaFold pLDDT 94.63 · 12 PDB
Residue 214: the 'methylenetetrahydrofolate dehydrogenase and methenyltetrahydrofolate cyclohydrolase (d/c) domain' region; a β-strand

Full MTHFD1 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

MTHFD1 p.Arg37His Uncertain significance ★★ ⚠ same condition
MTHFD1 p.Arg889Cys Uncertain significance ★★ ⚠ same condition
MTHFD1 p.Arg892Cys Uncertain significance ★★ same condition
MTHFD1 p.Asn207Tyr Uncertain significance ★★ ⚠ same condition
MTHFD1 p.Asp91Val Uncertain significance ★★ ⚠ same condition
MTHFD1 p.His644Arg Uncertain significance ★★ ⚠ same condition
MTHFD1 p.His693Gln Uncertain significance ★★ ⚠ same condition
MTHFD1 p.Ile40Met Uncertain significance ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/mthfd1-p-val214phe (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown